Ferula sinkiangensis (Chou-AWei, Chinese Ferula): Traditional Uses, Phytoconstituents, Biosynthesis, and Pharmacological Activities

Ferula is the third largest genus of the Apiaceae family, its species are utilized as a remedy for diverse ailments all over the world. F. sinkiangensis K. M. Shen (Chou-AWei, Chinese Ferula) is mainly found in Xin-jiang Uygur Autonomous Region, China. Traditionally, it is utilized for treating various illnesses such as digestive disorders, rheumatoid arthritis, wound infection, baldness, bronchitis, ovarian cysts, intestinal worms, diarrhea, malaria, abdominal mass, cold, measles, and bronchitis. It can produce different classes of metabolites such as sesquiterpene coumarins, steroidal esters, lignans, phenylpropanoids, sesquiterpenes, monoterpenes, coumarins, organic acid glycosides, and sulfur-containing compounds with prominent bioactivities. The objective of this work is to point out the reported data on F. sinkiangensis, including traditional uses, phytoconstituents, biosynthesis, and bioactivities. In the current work, 194 metabolites were reported from F. sinkiangensis in the period from 1987 to the end of 2022. Nevertheless, future work should be directed to conduct in vivo, mechanistic, and clinical assessments of this plant`s metabolites to confirm its safe usage.


Introduction
People have utilized plants since ancient times for different reasons: food, clothing, shelter, decoration, and construction [1]. Their usage by local and indigenous communities has been vertically and orally transferred among generations [2]. Also, plants are dynamic factories for the production of enormous kinds of metabolites. The plants and/or their metabolites form the backbone for diverse pharmaceutics, perfume, cosmetic, agrochemical, and food industries. Besides, they are traditional remedies for many ailments in various countries particularly the developed ones [3,4].
Ferula is the third largest genus of Apiaceae family that comprises about 180 species. Its species commonly exist in Asian and Mediterranean regions e.g., Iran, Turkey, Algeria, Afghanistan, Saudi Arabia, Pakistan, China, and India [5]. Ferula means "carrier" or "vehicle" in Latin and this genus is distinguished by the existence of oleo-gum-resins (e.g., sagapenum, asafoetida, ammoniacum, and galbanum) [6]. Most of its plants are with a pungent odor and bitter taste due to the existence of disulfides [7]. In Asia, they are utilized as a spice and in pickles, meat sauces, curry, and other foods as flavoring agents [7]. In China, the Ferula resin is employed for treating dysentery, worms, and malaria, and for more than thousand years in treating epilepsy, asthma, stom intestinal parasites, flatulence, influenza, dysentery, and weak dig tries [10]. These plants displayed a myriad of bioactivities: antic tiepileptic, antioxidant, antiulcer, antimicrobial, antihypertensive sant, antiproliferative, antiprotozoal, antihemolytic, antimycobac tifertility, antispasmodic, anticonvulsant, relaxant, antinocicep and digestive enzyme enhancing, antiviral, anxiolytics, antihy toxic, anti-inflammatory, antihyperglycemic, antidiabetic, and h They also demonstrated aphicidal, phytotoxic, and acaricidal a stated that sesquiterpene coumarins, coumarins, aromatic acid penes are the prime phytoconstituents of Ferula plants roots [11,1 and monoterpenes and their oxygenated derivatives with diver principal metabolites of Ferula species aerial parts oil [15].
It is worth reporting that the improper practice of wild plan and devasting to the naturally existing medicinal plants which menace to these substantial plants and may result in the extinctio cies [16]. Thus, the conservation of land resources and responsibl duction are the challenges in sustainable land resources usage [1 F. sinkiangensis K.M. Shen (Chou-AWei, Chinese Ferula, (X portant member of this genus. F. sinkiangensis is a perennial pl Uygur Autonomous Region, China [17] (Figure 1). It was reported that this plant is in the menace of evanescen building, unconstrained mining, reclamation, climate variation, a rioration, leading to annual shrinkage of F. sinkiangensis resour It was reported that this plant is in the menace of evanescence due to irrigation, road building, unconstrained mining, reclamation, climate variation, and original habitat deterioration, leading to annual shrinkage of F. sinkiangensis resources [18]. This plant was included among 2nd class protected wild medicinal species and 3rd class endangered plant in China [19,20]. However, this plant has not yet been included in the IUCN Red List of threatened species, as well as in CITES (Convention on International Trade in Endangered Species of Wild Fauna and Flora) [21][22][23].
The plant and its phytoconstituents revealed various bioactivities such as anti-ulcerative, antibacterial, anti-inflammatory, antioxidant, molluscicidal, anti-schistosome, anti-drug addiction, immunopharmacological, anti-neuroinflammatory, anticancer, antifungal, antiviral, and insecticidal [11,14,[25][26][27][28][29][30][31][32]. It is noteworthy that there is no current inclusive review on this plant. Since 1987, many studies were performed revealing new metabolites with diverse structural variation and promising activities from this plant. In this work, the reported studies on this plant, including traditional uses, its metabolites, their structural classes, biosynthesis, and bioactivities are reviewed. Overall, this work intended to give an inclusive introduction to F. sinkiangensis that could help in identifying the future investigations direction and possible implementations of this valuable medicinal plant.

Research Methodology
To collect the reported data on F. sinkiangensis, a comprehensive search was carried out on PubMed (37 records) and Google-scholar (529 records) databases, as well as the published articles by various publishers, including Springer, Elsevier, Taylor & Francis, Wiley, MDPI, Thieme, Hindawi, etc. The search keywords were F. sinkiangensis, ethnomedicinal uses, folk uses, bioactive compounds, biosynthesis, phytochemistry, biological activity, and pharmacology.
The selection criteria of the records including in this work were: (1) research articles had to be published in scientific journals (2) studies that reported the traditional uses, metabolites, biosynthesis, and bioactivities of F. sinkiangensis (3) patents, book chapters, and conferences. The covered records in this work included the published articles from various publishers, patents, book chapters, and conferences in the period from 1987 to the end of 2022. For the non-English articles, English abstracts have been utilized. The studies that did not agree with the selection criteria, as well as the whole non-English, non-reviewed, and not journal articles are excluded. In the current work, 72 references have been cited including articles from various publishers, books, conferences, webpages, and patents ( Figure 2).

Traditional Uses of F. sinkiangensis
F. sinkiangensis is mainly found in Xinjiang, which is a region with various minorities. The plant has been described in the Chinese Pharmacopoeia and in "Medica of the Tang Dynasty" for a long time as a folk medicine for gastric disorders and rheumatoid arthritis [24].
The resin of the roots or stems of F. sinkiangensis (Ferulae Resina, "AWei" in China) is a folk medicine recorded in Chinese Pharmacopoeia [25]. It is often utilized for reducing the symptoms of lumps, indigestion, joint pain, wound infection, baldness, bronchitis, and ovarian cysts by Uygur people in Xinjiang [25,[33][34][35]. It also is efficient in killing intestinal worms, as well as treating parasite-caused malnutrition, abdominal and stomachic swelling pain, diarrhea, malaria, abdominal mass, cold, and measles. However, its powerful odor has restricted its usage [36,37]. The resin is indicated in treating animal stagnation and food accumulation, concertions and conglomerations because of blood stasis, abdominal syndrome, and abdominal pain due to accumulation of worms, also for malaria and dysentery [38] at doses 1-1.5 g in the form of pills or oral powder. The resin should not be decocted with H 2 O [38]. Its use is prohibited for patients with spleen and stomach weakness, as well as for pregnant women [36,38].

Phytoconstituents of F. sinkiangensis
The phytochemical investigation of different parts of F. sinkiangensis, including gum resin, aerial parts, seed, roots, oleo-gum-resin, and resins led to the separation of different classes of phytoconstituents by the mean of diverse chromatographic tools (Table S1). Their structure characterization was performed using various spectral techniques (e.g., UV, NMR, MS), as well as CD, [α] D , and Xray analyses and chemical means. A total of 194 metabolites were separated from F. sinkiangensis (excluding polysaccharides). These metabolites were highlighted below.

Sesquiterpene Coumarins
The reported studies showed that sesquiterpene coumarins represent the major metabolites produced by this plant. They represent 60 metabolites (Figures 3-8) of the total compounds reported from this plant that were mainly separated from gum resin, seed, roots, and resins. It was noted that no sesquiterpene coumarin derivatives were reported from the aerial parts. worms, as well as treating parasite-caused malnutrition, abdominal and stomachic swell ing pain, diarrhea, malaria, abdominal mass, cold, and measles. However, its powerfu odor has restricted its usage [36,37]. The resin is indicated in treating animal stagnation and food accumulation, concertions and conglomerations because of blood stasis, ab dominal syndrome, and abdominal pain due to accumulation of worms, also for malaria and dysentery [38] at doses 1-1.5 g in the form of pills or oral powder. The resin should not be decocted with H2O [38]. Its use is prohibited for patients with spleen and stomach weakness, as well as for pregnant women [36,38].

Phytoconstituents of F. sinkiangensis
The phytochemical investigation of different parts of F. sinkiangensis, including gum resin, aerial parts, seed, roots, oleo-gum-resin, and resins led to the separation of differen classes of phytoconstituents by the mean of diverse chromatographic tools (Table S1) Their structure characterization was performed using various spectral techniques (e.g. UV, NMR, MS), as well as CD, [α]D, and Xray analyses and chemical means. A total of 194 metabolites were separated from F. sinkiangensis (excluding polysaccharides). These me tabolites were highlighted below.

Sesquiterpene Coumarins
The reported studies showed that sesquiterpene coumarins represent the major me tabolites produced by this plant. They represent 60 metabolites (Figures 3-8) of the tota compounds reported from this plant that were mainly separated from gum resin, seed roots, and resins. It was noted that no sesquiterpene coumarin derivatives were reported from the aerial parts. These compounds featured linked coumarin and sesquiterpene units through C-O-C ether bridge. These metabolites include monocyclic, bicyclic, or chain derivatives. Also they could be accountable for many of the stated bioactivities of this plant.  Their separation was performed by different chromatographic techniques, including SiO2/RP-18/Sephadex LH-20/HPLC, whereas the identification and configuration were accomplished using assort spectral tools (e.g., UV, NMR, MS), as well as CD, [α]D and Xray analyses. They had UV absorbance at 320-330 nm and a common fragment at m/z 185 in MS [39].

Sesquiterpene Chromones and Monoterpene Coumarins
Sesquiterpene chromones possessing a 24-carbon skeleton consisting of sesquiterpene and chromone were reported from F. sinkiangensis roots. In 2022, Wang et al. reported the purification of new derivatives, (±)-ferulasin from the roots MeOH extract that was established by diverse spectral, Xray, and ECD analyses. Ferulasins (61 and 62) showed an unusual oxygen-bearing macrocyclic skeleton with a tri-oxaspiro unit and a new backbone in which the C-10` and C-11` of the sesquiterpene side chain form an oxygen-including 13-membered ring with C-2 of chromone ( Figure 9). It was obtained as an enantiomeric mixture that was chiral-separated by HPLC to (+)-61 and (-)-62 with 2R/3R/10`R and 2S/3S/10`S configurations, respectively based on Xray and ECD data [40]. Wang et al. assumed the biosynthesis of 61 and 62 from ferulaeone A (71). The reduction of the 71-side chain C-3 produces 6-membered ring containing oxygen (Scheme 1). After that, the side chain C2`-C3` is oxidized and yields a 6-membered ring having oxygen with C-2 of chromone. After the six-membered ring fission, C10`-C11` bond reacts with ozone. These compounds featured linked coumarin and sesquiterpene units through C-O-C ether bridge. These metabolites include monocyclic, bicyclic, or chain derivatives. Also, they could be accountable for many of the stated bioactivities of this plant.
Their separation was performed by different chromatographic techniques, including SiO 2 /RP-18/Sephadex LH-20/HPLC, whereas the identification and configuration were accomplished using assort spectral tools (e.g., UV, NMR, MS), as well as CD, [α] D and Xray analyses. They had UV absorbance at 320-330 nm and a common fragment at m/z 185 in MS [39].

Sesquiterpene Chromones and Monoterpene Coumarins
Sesquiterpene chromones possessing a 24-carbon skeleton consisting of sesquiterpene and chromone were reported from F. sinkiangensis roots. In 2022, Wang et al., reported the purification of new derivatives, (±)-ferulasin from the roots MeOH extract that was established by diverse spectral, Xray, and ECD analyses. Ferulasins (61 and 62) showed an unusual oxygen-bearing macrocyclic skeleton with a tri-oxaspiro unit and a new backbone in which the C-10' and C-11' of the sesquiterpene side chain form an oxygen-including 13-membered ring with C-2 of chromone ( Figure 9). It was obtained as an enantiomeric mixture that was chiral-separated by HPLC to (+)-61 and (-)-62 with 2R/3R/10'R and 2S/3S/10'S configurations, respectively based on Xray and ECD data [40]. Wang et al., assumed the biosynthesis of 61 and 62 from ferulaeone A (71). The reduction of the 71side chain C-3 produces 6-membered ring containing oxygen (Scheme 1). After that, the side chain C2'-C3' is oxidized and yields a 6-membered ring having oxygen with C-2 of chromone. After the six-membered ring fission, C10'-C11' bond reacts with ozone. Lastly, attack of oxygen-atoms to C2-C3 the double bond from below or above the plane with removal of H 2 O a molecule to afford 61 and 62 (Scheme 1). Scheme 1. Biosynthetic pathway of (±)-ferulasin [40].
Additionally, ferusinkin A (63), a rare new monoterpene coumarin an logs 64 and 65 were purified and identified by Liu et al. in 2020 from the aeria extract ( Figure 9) [41].

Coumarins
The coumarins; 66 and 67 were purified from the F. sinkiangensis ae characterized based on spectral and physical data [41]. Additionally, sinki Lastly, attack of oxygen-atoms to C2-C3 the double bond from below or above the plane with removal of H2O a molecule to afford 61 and 62 (Scheme 1).
Additionally, ferusinkin A (63), a rare new monoterpene coumarin and known analogs 64 and 65 were purified and identified by Liu et al. in 2020 from the aerial parts MeOH extract ( Figure 9) [41].

Coumarins
The coumarins; 66 and 67 were purified from the F. sinkiangensis aerial parts and characterized based on spectral and physical data [41]. Additionally, sinkiangenol F (68) a new coumarin was purified from the resin EtOH extract. This compound is rare coumarin derivative having a coumarin unit connected to phenylethane moiety by C-C linkage at C-8 [39].
Plants 2023, 12, x FOR PEER REVIEW 10 of 33 a new coumarin was purified from the resin EtOH extract. This compound is rare coumarin derivative having a coumarin unit connected to phenylethane moiety by C-C linkage at C-8 [39].

Lignans
Lignans, norlignans, and sesquilignans were reported mainly from F. sinkiangensis The chiral column HPLC separation afforded their (-)-and (+)-antipodes. Their structures and configurations were specified by spectral tools and computational methods [28].
Sesquilignans are type of lignans that consist of 3 phenylpropanoid units. Compound 94 was assumed to be biosynthesized by the shikimate pathway (Scheme 2). First, phenylpropanoid is formed by a shikimic acid pathway that undergoes polymerization to produce intermediate A (aryltetralin lignan). In addition, intermediate C with a new six-membered ring skeleton is yielded from the intermediates A and B by the Diesel-Alder cycloaddition reaction. Moreover, C produces D by opening the ring at C1−C7. Subsequent oxidization and decarboxylation of D yields E. After a set of redox reactions, intermediate E gives 94 [44].
Sinkianlignans G-K (102-111) new norneolignans were purified from 95% resin EtOH extract utilizing SiO 2 /RP-18/MCI gel CHP 20P/Sephadex LH-20/preparative TLC ( Figure 14). Compounds 102-111 were obtained as racemic mixtures that were separated by chiral HPLC and characterized by spectral and computational means [18]. Plants 2023, 12, x FOR PEER REVIEW 12 of 33  Sesquilignans are type of lignans that consist of 3 phenylpropanoid units. Compound 94 was assumed to be biosynthesized by the shikimate pathway (Scheme 2). First, phenylpropanoid is formed by a shikimic acid pathway that undergoes polymerization to produce intermediate A (aryltetralin lignan). In addition, intermediate C with a new sixmembered ring skeleton is yielded from the intermediates A and B by the Diesel-Alder  Sesquilignans are type of lignans that consist of 3 phenylpropanoid units. Compound 94 was assumed to be biosynthesized by the shikimate pathway (Scheme 2). First, phenylpropanoid is formed by a shikimic acid pathway that undergoes polymerization to produce intermediate A (aryltetralin lignan). In addition, intermediate C with a new sixmembered ring skeleton is yielded from the intermediates A and B by the Diesel-Alder cycloaddition reaction. Moreover, C produces D by opening the ring at C1−C7. Subsequent oxidization and decarboxylation of D yields E. After a set of redox reactions, intermediate E gives 94 [44].

Sulfanes
It was reported that polysulfides including disulfanes, trisulfanes, di-d thio-disulfanes are the predominant constituents of the F. sinkiangensis vo gum resins. The oil content was 16.7% of which 64.1% were sulfur compoun fanes were the prime components: 126-130, 134, and 135 ( Figure 16) [8]. Fu MS analysis of essential oil (3.8% yield) of F. sikiangensis seeds obtained f China that was prepared by hydro-distillation method revealed the existenc olites, comprising 99.001% of total oil [33].

Sulfanes
It was reported that polysulfides including disulfanes, trisulfanes, di-disulfanes, and thio-disulfanes are the predominant constituents of the F. sinkiangensis volatile oil oleo-gum resins. The oil content was 16.7% of which 64.1% were sulfur compounds. The disulfanes were the prime components: 126-130, 134, and 135 ( Figure 16) [8]. Further, the GC-MS analysis of essential oil (3.8% yield) of F. sikiangensis seeds obtained from Xinjiang, China that was prepared by hydro-distillation method revealed the existence of 26 metabolites, comprising 99.001% of total oil [33].
These metabolites have an unparallel carbon framework that originates from C21steroids (Scheme 3). Firstly, the initiation of D-ring rearrangement by C8-C14 pregnane epoxide formation, then C-8 carbocation formation. After that, Wagner-Meerwein rearrangement results in a C14-15 bond migration to C-8 and the creation of a C-14 protonated carbonyl that is deprotonated [45]. Following that set of enzyme-catalyzed reactions produce 148 and 149 [17].

Phenolic Compounds and Other Metabolites
Several studies reported the separation of phenolics metabolites such as flavonoids, phenylpropanoids, and acids from resin and seed extracts (Figures 18 and 19) [18,24,27,29].
It was reported that polysulfides including disulfanes, trisulfanes, di-disulfanes, and thio-disulfanes are the predominant constituents of the F. sinkiangensis volatile oil oleogum resins. The oil content was 16.7% of which 64.1% were sulfur compounds. The disulfanes were the prime components: 126-130, 134, and 135 ( Figure 16) [8]. Further, the GC-MS analysis of essential oil (3.8% yield) of F. sikiangensis seeds obtained from Xinjiang, China that was prepared by hydro-distillation method revealed the existence of 26 metabolites, comprising 99.001% of total oil [33].
In another study, the sequential extraction of F. sinkiangensis roots yielded 28.86 wt% total polysaccharides. The polysaccharide fractions are heteropolysaccharides, containing galacturonic and glucuronic acids, galactose, xylose, rhamnose, fructose, and arabinose [47].  [48]. Structure-activity relationship revealed that the substitution at C-3' in the bicyclic derivatives that possess 8'R-CH 3 and 8'R-OH had a substantial role in the activity. The capability of C-3'-substitutents to boost the effect followed this order: acetoxy, α-OH, β-OH, and C=O, however, this order varied in bicyclic derivatives with C-8' terminal olefinic bond. In the mono-cyclic derivatives, the rings' breaking position of sesquiterpene moiety could influence the efficacy e.g., 32 and 33 with broken A-ring were more active than 39 and 41 with broken B-ring. Besides, the O-bridge in ring A in monocyclic derivatives improved the efficacy. On the other hand, the chain derivatives (e.g., 57 and 52) had weak activity [48]. In 2020, Zhang et al., evaluated the potential of 12 on ischemic stroke utilizing BCCAO (bilateral common carotid artery occlusion) and LPS-invigorated microglia models. It was found that 12 relieved cognitive weakness, lowered neuronal forfeiture, repressed microglial stimulation, and converted microglia from the proinflammation M1 type to the anti-inflammation M2 type in the BCCAO-mice model. Moreover, it organized microglial polarization and suppressed the MAPK (mitogen-activated protein kinase) and NLRP3 signaling pathways subsequent to LPS-treatment in vitro. These findings highlighted the possible activity of 12 for treating ischemic stroke [49]. Further, in 2021, Mi et al., explored the potential of 12 on cerebral ischemia utilizing MCAO (middle-cerebral-artery occlusion) and LPS-boosted microglia models. In the MCAO model, 12 amended neurological outcomes and decreased infarct size and edema of the brain in rats. It also mitigated neuron injury and restrained microglial activation. Moreover, 12 guarded neuronal cells against damage by repressing microglial activation in LPS-invigorated BV2 cells. It also diminished the proinflammatory cytokines levels, NADPH oxidase activity, and ROS generation, along with the NF-κB signaling pathway repression [28].
Umbelliprenin (52) possessed dose-dependent and time-dependent apoptosis in CLL (chronic lymphocytic leukemia) that was more sensitive to 52 than PBMCs. It is noteworthy that IL-4 could not decline 52-caused apoptosis in CLL (Figure 7). Thus, 52 oral administration as foods or folk medicines, might stimulate the protection against CLL development with few side effects, however, additional clinical investigations are needed [53]. Gholami et al. reported that 52 potentiated apoptosis intrinsic/extrinsic pathways in Jurkat cells by activating caspase-9 and -8, as well as Bcl-2 prohibition [54]. Another study by Zhang et al. revealed that 52 had a notable anticancer activity (IC50s 13.67 and 20.82 µM, respectively) against AGS cells with less anticancer to GES-1 (normal human gastric epithelial cell line). It boosted AGS cells apoptosis with elevated Bax/Bcl-2 ratios, ROS generation, lessened mitochondrial-membrane potential, and PARP and caspase 3 activation resulting in mitochondrial apoptosis pathway activation. It also arrested the G0/G1 phase of the cell cycle, increased P27, P53, and P16, expression, and diminished cyclin E, cyclin D, Cdk2, and Cdk4 expression in cancer cells. Therefore, it could be developed into anti-cancer therapy [24]. In 2019, Zhang et al. also reported that 52 also demonstrated anticancer capacity against BGC-823 and AGS, with less toxic influence on the normal GES-1 gastric cells. It was proven to prevent gastric cancer cell invasion, growth, and migration by disconcerting the Wnt signaling pathway. Additionally, it exhibited no harm in the in vivo BGC-823 xenograft model as evidenced by no observed abnormality in daily diet, body weight, liver function, and histological features of the spleen, liver, lung, kidney, and heart tissue. This further supported the previous evidence of its promising potential for treating gastric cancer [55].
Umbelliprenin (52) possessed dose-dependent and time-dependent apoptosis in CLL (chronic lymphocytic leukemia) that was more sensitive to 52 than PBMCs. It is noteworthy that IL-4 could not decline 52-caused apoptosis in CLL (Figure 7). Thus, 52 oral administration as foods or folk medicines, might stimulate the protection against CLL development with few side effects, however, additional clinical investigations are needed [53]. Gholami et al., reported that 52 potentiated apoptosis intrinsic/extrinsic pathways in Jurkat cells by activating caspase-9 and -8, as well as Bcl-2 prohibition [54]. Another study by Zhang et al., revealed that 52 had a notable anticancer activity (IC 50 s 13.67 and 20.82 µM, respectively) against AGS cells with less anticancer to GES-1 (normal human gastric epithelial cell line). It boosted AGS cells apoptosis with elevated Bax/Bcl-2 ratios, ROS generation, lessened mitochondrial-membrane potential, and PARP and caspase 3 activation resulting in mitochondrial apoptosis pathway activation. It also arrested the G0/G1 phase of the cell cycle, increased P27, P53, and P16, expression, and diminished cyclin E, cyclin D, Cdk2, and Cdk4 expression in cancer cells. Therefore, it could be developed into anti-cancer therapy [24]. In 2019, Zhang et al., also reported that 52 also demonstrated anticancer capacity against BGC-823 and AGS, with less toxic influence on the normal GES-1 gastric cells. It was proven to prevent gastric cancer cell invasion, growth, and migration by disconcerting the Wnt signaling pathway. Additionally, it exhibited no harm in the in vivo BGC-823 xenograft model as evidenced by no observed abnormality in daily diet, body weight, liver function, and histological features of the spleen, liver, lung, kidney, and heart tissue. This further supported the previous evidence of its promising potential for treating gastric cancer [55].
In the CCK-8 assay, 84 and 86 were found to significantly prohibit the migration and invasion of TNBC) cell lines. On the other hand, 88 and 89 promoted the HUVECs) proliferation which was more remarkable than bFGF (basic-fibroblast-growth factor, positive control) in the wound-healing assay [35].
The petroleum ether, EtOAc, n-BuOH, and MeOH fraction possessed of F. sinkiangensis resin anticancer activity against Caco-2, HC-T116, MFC, and HepG2 cells in the SRB assay. EtOAc fraction was found to have the potent anti-proliferative and apoptotic effects against all tested cell lines. This was correlated to its content of sesquiterpene coumarins [31].

Anti-Drug Addiction Activity
Drug addiction is a prime health concern that influences a growing number of persons and gives rise to severe economic and social burdens to economy society [56,57]. Despite the fact that diverse remedial strategies for drug addiction and abuse are developed, including psychological, sociological, and pharmacological interventions, their activity is yet restricted [58,59].
A mixture of 133 and 135 was obtained from the F. sinkiangensis crude essential oil. A mixture of 133 and 135 (1:3 ratio, doses: 20, 40, and 60 mg/kg, ip) significantly repressed the morphine abstinence syndrome and physiological addiction in rats and mice [60]. At the same doses, this mixture (1:3 ratio, i.p.) reduced morphine-induced bodyweight loss. While the mixture declined the abdominal writhing movements number and automatic activity (doses 10.73, 21.45, and 43.55 mg/kg, i.p.) revealing its analgesic and sedative potential. Its acute toxicity evaluation showed the LD 50 values of its iv and ip injections were 1.42 g/kg and 1.66 g/kg, respectively [60].
In 2006, Wang reported in his patent that the resin extract in the form of capsules, powder, injection, drop pills, granules, tablets, or oral liquid) ameliorated the influences of serious and moderate long-time drug addictions in addicted patients, indicating its potential for treating subjects addicted to morphine, opioid, diamorphine, and marijuana [36,38]. It is noteworthy that 0.1-20 g/kg was found to be the therapeutically effective amount of the extract for producing an effect of abstinence of morphine, whereas the preferable dose was 1-3 g/kg [36].

Protein-Tyrosine Phosphatase 1B Inhibition Activity
FSPs-a (acidic polysaccharides) fraction of F. sinkiangensis roots water-soluble polysaccharides revealed in vitro PTP1B (protein-tyrosine phosphatase 1B) competitive inhibition (IC 50 0.29 µg/mL, % inhibition 91.23%) [34]. In another study, the PTP1B inhibitory potential of the different polysaccharides fractions was estimated. It was noted that the inhibitory capacity of the tested fractions elevated with raising their galactose content, therefore, galactose may be a ligand for blocking PTP1B catalytic site [47].

Antiulcer and Antioxidant Activities
In the in vivo antiulcer assay, different F. sinkiangensis resin extracts possessed antiulcer capacity, whereas CHCl 3 extract (%inhibition 48.43) had comparatively better antiulcer potential than the n-BuOH and EtOAC (%inhibition 37.07 and 46.06%, respectively) extracts comparing to famotidine (%inhibition 45.37) [14]. In the DPPH assay, the F. sinkiangensis resin n-BuOH, EtOAc, and MeOH fractions significantly scavenged DPPH, whereas the EtOAc fraction was the most effective and the petroleum ether fraction was weakly active in the DPPH assay [31].

Feed Attraction Activity
In 2020, Xu et al., reported that feeding Lateolabrax japonicus (commercial fish) with F. sinkiangensis was found to notably promote L. japonicus foraging and better digestive enzyme activity and fish growth performance, where 10 g/kg was appropriate in the fish diet. Thus, it had an efficient role in L. japonicus farming and could have potential in the aquaculture industry as aquafeed formulation [61].

Traditional Ethnomedicinal Uses in Asian Countries
Medicinal plants are fundamental to humans and utilized for thousands of years in various cultures to treat or prevent diseases or promote health and well-being [62]. Many communities continue to depend on plants as the main tool for healing various illnesses and have established their medical systems on the basis of their unique beliefs, experiences, and theories worldwide [63]. Traditional and indigenous medical systems are especially widespread throughout communities in Asia that are accountable for a remarkable proportion of the healthcare provided in these countries [64,65]. Ayurveda, Jamu, traditional Philippines, traditional Malay, Sowa Rigpa, Tibetan, Kampo, Siddha, Thai medicine, Unani, and traditional Chinese systems are important sources of livelihood and health for millions of Asian people [62,66]. Generally, the region's traditional medicine systems are greatly affected by those practiced in the neighboring areas especially of South and East Asia, mainly that of India and China [62]. In China, different sociolinguistic groups have their own traditional systems and medicinal plant usages that vary based on associated ecology and geography [67]

Conclusions
Herbal medicines have been utilized for thousands of years as principal therapeutic agents for treating various human illnesses in many countries. Recently, a growing number of studies have been carried out to prove the efficacy of these medicines against the assigned disorders. F. sinkiangensis is among the most valuable species of the genus Ferula that possess various traditional applications in treating various disorders such as bronchitis, diarrhea, malaria, gastric disorders, and rheumatoid arthritis. In this work, 194 metabolites have been characterized from various parts of this plant, including aerial parts, seed, roots, gum resin, oleo-gum resin, and resins ( Figure 21). plants) is renowned for its large variety of ethnic groups with featured traditional cultures. Populations from 33 ethnicities are using plants as a traditional remedy for thousands of years, including Bai, Achang, Bulang, Tibetan, Buyi, Dai, Dong, De'ang, Hani, Dulong, Hui, Han, Jinuo, Lahu, Jingpo, Lisu, Maonan, Luoba, Menba, Molao, Miao, Naxi, Pumi, Nu, Qiang, Shui, She, Tujia, Yao, Wa, Yi, Zhuang, and Gelao people [67,68].

Conclusions
Herbal medicines have been utilized for thousands of years as principal therapeutic agents for treating various human illnesses in many countries. Recently, a growing number of studies have been carried out to prove the efficacy of these medicines against the assigned disorders. F. sinkiangensis is among the most valuable species of the genus Ferula that possess various traditional applications in treating various disorders such as bronchitis, diarrhea, malaria, gastric disorders, and rheumatoid arthritis. In this work, 194 metabolites have been characterized from various parts of this plant, including aerial parts, seed, roots, gum resin, oleo-gum resin, and resins ( Figure 21). It was obvious that the majority of metabolites have been distinguished from resin extract. These metabolites belong to various chemical classes. Sesquiterpene coumarins with their structural diversity and contents represent the main and substantial metabolites of this plant ( Figure 22). It was obvious that the majority of metabolites have been distinguished from resin extract. These metabolites belong to various chemical classes. Sesquiterpene coumarins with their structural diversity and contents represent the main and substantial metabolites of this plant ( Figure 22). Many studies surmised that these compounds may have a substantial contribution in many of the reported activities of F. sinkiangensis. F. sinkiangensis had metabolites with marked antifungal and insecticidal capacity that can be valuable in agriculture for insect and plant pathogens control, however, additional field assessment is requested. Its metabolites; 61, 62, 65, 70, and 120 had notable anticancer potential against different cancer Many studies surmised that these compounds may have a substantial contribution in many of the reported activities of F. sinkiangensis. F. sinkiangensis had metabolites with marked antifungal and insecticidal capacity that can be valuable in agriculture for insect and plant pathogens control, however, additional field assessment is requested. Its metabolites; 61, 62, 65, 70, and 120 had notable anticancer potential against different cancer cell lines. These findings would provide evidence for the application of this and its fractions in treating cancers. Compound 12 had marked anti-inflammatory and anti-neuroinflammatory potential, revealing its potential as a lead metabolite for therapeutic intervention in various illnesses such as ischemic stroke, Alzheimer's disease, and cerebral ischemia. Many studies proved the anticancer and apoptotic potential of 52 against different cancer cell lines particularly the gastric cancer cells with no toxic effect on the normal cells and no observed abnormality in daily diet, body weight, liver function, and histological features of the spleen, liver, lung, kidney, and heart tissue. This further supported its promising potential for treating gastric cancer as foods or folk medicine, however, additional clinical investigations are needed. To find out more metabolites with unique structures and bioactivity, more phytochemical investigations are demanded and indispensable. Also, new technologies such as metabolomics, transcriptomics, genomics, and proteomics can be applied for discovering more metabolites from this valuable medicinal plant. The plant's mechanism in treating gastric disorders and rheumatoid arthritis is insufficiently explored. Additionally, in-depth in-vivo and in vitro studies of the other bio-activities mechanisms are required. Meanwhile, toxicological, pharmacokinetic, preclinical, quality control, and clinical studies are insistent to estimate the safety and rationale usage of this plant. Finally, the integration of traditional knowledge into ecology-based research for the endangered medicinal plant protection must be promoted.

Conflicts of Interest:
The authors declare no conflict of interest.

1D NMR
One-dimensional nuclear magnetic resonance 2D NMR Two-dimensional nuclear magnetic resonance A549 Human lung adenocarcinoma epithelial cell line AGS Human gastric carcinoma cell line Bax/Bcl-2 B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) BCCAO Bilateral common carotid artery occlusion 1D NMR One-dimensional nuclear magnetic resonance 2D NMR Two-dimensional nuclear magnetic resonance A549 Human